Studies in Cote D'lvoire found that trimethoprim-sulfamethoxazole (TS) reduced hospitalizations and mortality among HIV-infected persons who were not receiving antiretroviral therapy. TS shares its mechanism of action with sulfadoxine-pyrimethamine (SP) and other antifolate drugs used to treat malaria. In vitro resistance to the antifolates in Plasmodium falciparum is caused by point mutations in the enzymes targeted by these drugs, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS). TS prophyaxis is expected to select for resistance-conferring DHFR and DHPS mutations in P. falciparum. Where HIV and malaria are both common, this selection may accelerate development of malaria resistance to SP, both at the population level and at the individual level. The latter is of special concern, since HIV-infected persons on TS prophylaxis who are infected with falciparum malaria may be more likely to fail SP treatment and progress to severe malaria disease and death. The risks and benefits of TS prophylaxis in persons on antiretroviral therapy are unknown, and this has been identified as a research priority by health policymakers in Malawi, where in vitro TS resistance of infections prevented by TS prophylaxis is very high. Our primary aim is to determine if TS prophylaxis leads to increased SP resistant malaria. We will conduct a prospective, double blind, placebo controlled study among adults on antiretroviral therapy in Malawi. Clinical and parasitological responses to SP treatment for malaria will be monitored and selective effects of TS prophylaxis on resistance-conferring DHFR and DHPS mutations will be assessed. As a secondary aim, the efficacy of TS prophylaxis at preventing disease and death will be measured. These studies are expected to add to our knowledge of the molecular basis of antifolate-resistant malaria and to provide information of direct and immediate relevance to HIV and malaria control policies in Africa. [unreadable] [unreadable]